Various benzazepine and benzothiazepine derivatives display, for example, vasodilating activity. (See, e.g., U.S. Pat. Nos. 4,774,239; 4,767,756; 4,771,047; 4,694,002; 4,752,645; 4,748,239; and 4,584,131.) Useful benzazepine and benzothiazepine compounds can be described by the formula ##STR1## wherein, in formula I and throughout the specification, X.sub.1 is --CH.sub.2 -- or --S--;
R.sub.1 is ##STR2## hydrogen, alkyl, acetyl, aryl, alkenyl, alkynyl, arylalkyl, --SR.sub.9, --N.sub.3, --NH.sub.2, ##STR3## when X.sub.1 is --S--, R.sub.2 is hydrogen, ##STR4## R.sub.3, R.sub.4 and R.sub.5 are each independently hydrogen, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, diarylalkoxy, arylalkyl, cyano, hydroxy, alkanoyloxy, nitro, ##STR5## fluoro-substituted alkoxy, fluro-substituted alkyl, (cycloalkyl)alkoxy, ##STR6## R.sub.6 is hydrogen, alkyl, acetyl, aryl, arylalkyl, or --NR.sub.7 R.sub.8 ; PA1 R.sub.7 and R.sub.8 are each independently hydrogen, alkyl, cycloalkyl, or arylalkyl; or R.sub.7 and R.sub.8, together with the nitrogen atom to which they are attached, are azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl; PA1 R.sub.9 is acyl, alkyl, aryl, or arylalkyl; PA1 R.sub.10 and R.sub.11 taken together are oxygen or R.sub.10 is hydrogen and R.sub.11 is hydroxy; PA1 R.sub.12 is hydrogen, hydroxy, alkyl, aryl, arylalkyl, --O--alkyl, --O--aryl, or --O--arylalkyl; PA1 R.sub.13 is hydrogen, alkyl, cycloalkyl, or arylalkyl; PA1 R.sub.14 is heterocyclo or heteroaryl; PA1 X.sub.2 is oxygen, sulfur, or a single bond when R.sub.6 is --NR.sub.7 R.sub.8 ; PA1 X.sub.3 is oxygen or sulfur; PA1 X.sub.4 and X.sub.5 are each independently hydrogen, alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl or --C--NR.sub.7 R.sub.8 ; PA1 X.sub.6 is hydroxy, alkoxy, aryloxy, amino, alkylamino, or dialkylamino; PA1 X.sub.7 is alkyl, alkoxy, or aryloxy; but if R.sub.3 is a 7-alkyl group, it must have a tertiary carbon atom bonded to the ring; PA1 Y.sub.1 and Y.sub.2 are each hydrogen or alkyl; or Y.sub.1 is hydrogen and Y.sub.2 is alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl; or Y.sub.1 and Y.sub.2, together with the carbon atom to which they are attached, are cycloalkyl; PA1 Y.sub.3 is hydrogen, alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl, or --C--NR.sub.7 R.sub.8 PA1 Y.sub.4 and Y.sub.5 are each independently hydrogen, alkyl, aryl or arylalkyl, provided that when both are present they are not both hydrogen, and provided further that when both are attached to the same carbon atom neither of them is hydrogen; PA1 Y.sub.6 is hydrogen, hydroxy, alkoxy, aryloxy, or aralkoxy; PA1 m is 0, 1, or 2; PA1 n or n' is 0, 1, 2, or 3; and PA1 q is an integer from 0 to 5. PA1 a lower alkyl of 1 to 4 carbons; PA1 a lower alkylthio of 1 to 4 carbons; PA1 a lower alkoxy of 1 to 4 carbons; PA1 a halo; PA1 a nitro; PA1 a keto; PA1 a cyano; PA1 a hydroxy; PA1 an amino; PA1 --NH-alkyl, wherein the alkyl is of 1 to 4 carbons; PA1 --N(alkyl).sub.2, wherein the alkyl is of 1 to 4 carbons; PA1 --CF.sub.3 ; PA1 NCS; or PA1 OCHF.sub.2.
Exemplary formula I compounds are ##STR7##
Exemplary formula I compounds are also described in, for example, U.S. Pat. No. 4,902,684.
The carbon atoms in the 3- and 4-positions of the benzazepine nucleus and in the 2- and 3-positions of the benzothiazepine nucleus of formula I compounds are asymmetric carbons. The compounds of formula I, therefore, exist in enantiomeric and diastereomeric forms and as racemic mixtures thereof. All are within the scope of formula I. It is believed that formula I compounds having the d-cis configuration are the most potent and are therefore preferred.
The following definitions apply throughout this specification, unless otherwise limited in specific instances.
The terms "alkyl" and "alkoxy" refer to both straight and branched chain groups. Those groups having 1 to 10 carbon atoms are preferred.
The terms "alkenyl" and "alkynyl" refer to both straight and branched chain groups. Those groups having 2 to 10 carbon atoms are preferred.
The term "aryl" refers to phenyl and substituted phenyl. Exemplary substituted phenyl groups are phenyl groups substituted with 1, 2 or 3 amino (--NH.sub.2), alkylamino, dialkylamino, nitro, halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), alkanoyloxy, carbamoyl or carboxyl groups.
The term "heteroaryl" refers to an aromatic heterocyclic group having at least one heteroatom in the ring. Preferred groups are pyridinyl, pyrrolyl, imidazolyl, furanyl, thienyl, or thiazolyl.
The term "heterocyclo" refers to fully saturated or unsaturated rings of 5 or 6 atoms containing one or two oxygen and sulfur atoms and/or one to four nitrogen atoms, provided that the total number of hetero atoms in the ring is 4 or less. The hetero ring is attached by way of an available carbon atom. The term "heterocyclo" also includes bicyclic rings wherein the five-or six-membered ring containing oxygen, sulfur, or nitrogen atoms as defined above is fused to a benzene ring and the bicyclic ring is attached by way of an available carbon atom in the benzene ring. The term "heterocyclo" further includes such monocyclic and bicyclic rings wherein an available carbon atom is substituted with:
The term "heterocyclo" further includes monocyclic and bicyclic rings wherein two or three available carbons have substituents selected from methyl, methoxy, methylthio, halo, CF.sub.3, nitro, hydroxy, amino, and OCHF.sub.2.
The term "cycloalkyl" refers to groups having 3, 4, 5, 6 or 7 carbon atoms.
The terms "halogen" and "halo" refer to fluorine, chlorine, bromine, iodine, and trifluoromethyl.
The terms "fluoro-substituted alkyl" and "fluoro-substituted alkoxy" refer to alkyl and alkoxy groups (as described above) in which one or more hydrogens have been replaced by fluorine atoms. Exemplary groups are trifluoromethyl, 2,2,2, -trifluoromethyl, pentafluoroethyl, fluoromethoxy, difluoromethoxy, etc.
The term "alkanoyl" refers to groups having the formula ##STR8## Those alkanoyl groups having 2 to 11 carbon atoms are preferred.
The compounds of formula I can be prepared by first reacting a 2-nitrotoluene having the formula ##STR9## with a benzylidine malonate having the formula ##STR10## wherein Y is alkyl. The reaction can be run in a polar nonprotic solvent (e.g., dimethylformamide), in the presence of a strong base (e.g., sodium hydride) and yields a product having the formula ##STR11##
Reduction of a compound of formula IV yields the corresponding compound having the formula ##STR12## The reduction can be accomplished by catalytic hydrogenation (using, for example, palladium on charcoal as a catalyst) or by using a chemical reducing agent (e.g., ferrous sulfate or stannous chloride).
Treatment of an amine of formula V with an alkali metal alkoxide (e.g., sodium methoxide) and an alcohol (e.g., methanol) or with potassium hexamethyldisilazide in a solvent such as tetrahydrofuran or toluene, yields the corresponding benzazepine having the formula ##STR13##
Reaction of a compound of formula VI with a reducing agent, such as lithium aluminum hydride, in a solvent such as tetrahydrofuran, at low temperature yields the corresponding compound having the formula ##STR14##
Compound VII can thereafter be reacted with p-toluenesulfonylchloride or methanesulfonylchloride in the presence of a base (e.g., pyridine) to provide a compound having the formula ##STR15##
Compound VIII can be reacted with a base in the presence of a solvent (e.g., dichloromethane or dimethylformamide) at room temperature to provide the corresponding compound having the formula ##STR16##
Compound IX may then be treated with an alkali metal hydride (e.g., sodium hydride) in an inert solvent (e.g., dimethylsulfoxide), followed by reaction with a compound having the formula
IX' EQU R.sub.2 -halogen
to form a compound having the formula ##STR17##
If compound X could be efficiently reduced at the 3-position, it could form the useful intermediate having the formula ##STR18##
In the prior art, compound XI could be formed by decarboxylation of a compound having the formula ##STR19## by treating compound XII with, for example, excess lithium iodide in hot pyridine. See U.S. Pat. No. 4,748,239. This process yields a mixture of compound XI and its isomer ##STR20##
Formula I compounds can be prepared from compounds XI and XI' as described in U.S. Pat. Nos. 4,584,131; 4,748,239; 4,752,645; 4,694,002; 4,771,047; 4,767,756; and 4,774,239. Further preparation of formula I compounds is described in U.S. patent application Ser. Nos. 208,521 (filed Jun. 20, 1988); 353,806, (filed May 22, 1989), now U.S. Pat. Nos. 4,902,684; and 334,025 (filed Apr. 6, 1989). For compounds wherein X.sub.1 is --S--, see U.S. Pat. Nos. 4,584,131 and 4,694,002.
Compound XI is preferred over compound XI' because compound XI is in the more potent d-cis configuration. A process that favors production of compound XI, therefore, would be a useful addition to the art.